Antibody to epiglycanin and radioimmunoassay to detect epiglycanin-related glycoproteins in body fluids of cancer patients.

By means of a radioimmunoassay, which utilized [125I]-epiglycanin and anti-epiglycanin antiserum induced in rabbits by injections of viable TA3-Ha ascites cells with Freund's complete adjuvant, picogram quantities of epiglycanin could be detected. Anti-epiglycanin antiserum was similarly produced in allogeneic mice. Unlabeled epiglycanin lost the capacity to compete with [125I]epiglycanin in the radioimmunoassay as a result of periodate oxidation or incubation with endo-alpha-N-acetyl-D-galactosaminidase (Diplococcus pneumoniae), an enzyme found to cleave only the disaccharide beta-D-galactopyranosyl-(1----3)-2-acetamido-2-deoxy-D-galactose chain from serine or threonine residues in epiglycanin. Glycosylhydrolases known to cleave alpha-D-mannose, beta-D-galactose (1,4-linked), beta-N-acetyl-D-glucosamine, and alpha-N-acetyl-D-galactosamine did not reduce the activity of epiglycanin. Neuraminidase enhanced the activity twofold to fivefold. The finding that little or no activity was demonstrated by the disaccharide, the reduced disaccharide, or other glycoproteins containing the same disaccharide chain suggested that the antigenic determinant probably involved the disaccharide and a unique amino acid sequence at the site of its attachment. By means of the radioimmunoassay epiglycanin cross-reactive antigens were detected in the peritoneal or pleural fluid and in the sera of patients with metastatic cancer. Lower concentrations of epiglycanin-like antigen(s) were found in the peritoneal fluid of patients with hepatitis or liver cirrhosis but not in normal serum.

A Phase I study of continuous infusion doxorubicin and paclitaxel chemotherapy with granulocyte colony-stimulating factor for relapsed epithelial ovarian cancer.

A Phase I study of paclitaxel and doxorubicin administered as concurrent 96-h continuous i.v. infusion was performed to determine the maximum tolerated dose (MTD), principal toxicities, and pharmacokinetics of this combination in women with relapsed epithelial ovarian cancer. The paclitaxel dose was fixed at 100 mg/m2 (25 mg/m2/day for 4 days). The dose of doxorubicin was escalated from 30 mg/m2 (7.5 mg/m2/day for 4 days) in increments of 10 mg/m2 until dose-limiting toxicity was observed. All patients received granulocyte colony-stimulating factor 5 microg/kg/day prophylactically. Apparent steady-state plasma levels of both drugs were determined in the final cohort of patients treated at the MTD. A total of 17 patients received 52 cycles of therapy. The median age was 58 years, and all patients had previously received one to five different regimens (median, 2) of chemotherapy, including both platinum and paclitaxel. The treatment was tolerated well, with grade 1-2 nausea being the most frequent side effect (73% of cycles). Anemia, neutropenia, thrombocytopenia, and mucositis became dose limiting at the fourth dose level, defining the MTD of doxorubicin in this regimen as 50 mg/m2. There were four partial responses and one complete response in 15 evaluable patients. Apparent steady-state plasma concentrations (mean +/- SD) of paclitaxel and doxorubicin in the three patients treated at the MTD were 33.9 +/- 12.5 nM and 15.7 +/- 1.3 nM, respectively. Paclitaxel and doxorubicin by continuous infusion is a well-tolerated and active chemotherapy regimen for recurrent ovarian cancer.

Sarcomas of the uterine corpus: prognostic factors and treatment.

Twenty-eight patients with sarcomas of the uterine corpus were followed at least 22 months or until death. All underwent laparotomy, eleven had radiation therapy, and six had chemotherapy. Three year actuarial survival was 24%, and three year actuarial local control was 36%. Multivariate analysis demonstrated that, as with sarcomas at other sites, the most important factors influencing survival were grade (P = 0.020) and stage (P = 0.022). For local control, multivariate analysis indicated the most important factors to be stage (P = 0.001) and radiation TDF (P = 0.01). Of 21 failures, 16 involved the pelvis, seven involved the upper abdomen, and 11 involved distant sites. The importance of both local and distant disease control is emphasized.

Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis.

OBJECTIVE: To evaluate the correlation between the diagnosis of borderline tumor of the ovary by frozen and permanent pathology. METHODS: All pathology reports with diagnoses of borderline tumor of the ovary between 1980 and 1998 at Massachusetts General Hospital were reviewed. Univariate and multivariable logistic regression models were constructed for patient age, tumor size, histology, presence of bilateral or extraovarian disease, and concurrent diagnosis of endometriosis or endosalpingiosis. RESULTS: We reviewed 140 cases. The average age of patients was 52.3 years. Eighty tumors were serous, 47 mucinous, 11 mixed, and two endometrioid. The mean diameter overall was 13.7 cm (range 1-70 cm), 10.2 cm for serous, and 20.1 cm for mucinous. Diagnoses of borderline tumors by frozen and permanent pathology were consistent in 60% of cases. Frozen section interpreted a benign lesion as malignant (overdiagnosed) in 10.7% of cases, and interpreted a malignant lesion as benign (underdiagnosed) in 29.3%. No variable was a significant predicator of overdiagnosis. In univariate analysis, underdiagnosis was more likely for other types of tumors than serous (P <.001), tumors larger than 20 cm (P =.039), and tumors confined to the ovaries (P =. 009). When all variables were included in a multiple regression model, only histology was a significant predictor of underdiagnosis (P =.039). CONCLUSION: Frozen or permanent pathology reports of diagnoses of borderline tumor were consistent 60% of the time, whereas the positive predictive value of borderline by frozen section was 89.3%. Tumors other than serous are more likely to be misinterpreted.

Prognostic importance of intraoperative rupture of malignant ovarian epithelial neoplasms.

OBJECTIVE: To determine whether rupture of malignant ovarian epithelial tumors at the time of operation influences the patient's overall prognosis. METHODS: Between 1975 and 1990, 79 patients with stage I invasive epithelial ovarian cancer were treated at Massachusetts General Hospital. Patients were identified from the tumor registry, and charts were reviewed retrospectively. In 71 of the 79 cases, pathologic slides were evaluated. Of the 79 patients, 36 had stage Ia tumors, 20 stage Ic secondary to intraoperative rupture (Ic-rupture), and 17 stage Ic secondary to capsular invasion-serosal disease or positive ascites or washings (stage Ic-other). Survival analysis was performed to compare the three groups of patients. RESULTS: There were four recurrences and deaths among the 20 women with stage Ic-rupture tumors (20%), compared to one (3%) among the 36 women with stage Ia. The recurrence-free survival at the median follow-up time for the two groups was 97 +/- 3 and 78 +/- 10 months, respectively (P = .03); overall survival was 97 +/- 3 and 73 +/- 12 months (P = .04). There were two recurrences (12%) and one death (6%) among the 17 women with stage Ic-other, giving recurrence-free and overall survivals of 88 +/- 8 and 94 +/- 6 months, respectively. The survival experience of this last group was not significantly different from that in the Ic-rupture group (P = .2). The hazard ratios for overall survival associated with stage Ic-rupture and each potential confounder, except for bloating, exceeded 6.5, with P < or = .10. All deaths occurred in the 28 patients with grade 2 or 3 tumors. Even in this smaller group, the hazard ratio for stage Ic-rupture was 6.8 (P = .09). CONCLUSION: Intraoperative rupture of malignant epithelial ovarian neoplasms may worsen the prognosis of patients with stage I ovarian cancer.

Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel.

In vitro work suggests that cytokines may be important modulators of the cytotoxic effects of paclitaxel and subsequent drug resistance. This has been investigated in vivo in patients with ovarian cancer by ELISA. There was consistently elevated expression of IL-6 and IL-8 but not MCP-1, IL-1beta, IL-2, GM-CSF or TNFalpha. Peritoneal fluid concentrations of IL-6, IL-8 and MCP-1 were two to three logs greater than serum concentrations. Elevated concentrations of IL-6 correlated with a poor final outcome (P = 0.039), and increased IL-6 and IL-8 correlated with a poor initial response to chemotherapy (P = 0.041 and P = 0.041, respectively). There was a relatively clear pattern of change in all three cytokines. In serum, IL-6, IL-8 and MCP-1 decreased with the administration of steroids prior to paclitaxel, and increased in the 24 h after paclitaxel. Postoperative drainage fluid was relatively acellular, preventing flow-cytometric analysis of epithelial cells for apoptosis, but suggested activation of T cells by paclitaxel. IL-6 and IL-8 appear to be of prognostic importance in epithelial ovarian cancer. Treatment with paclitaxel is associated with an increase in expression of a limited number of cytokines in patients with ovarian cancer, notably IL-6, IL-8 and MCP-1.

Fallopian tube carcinoma.

Primary fallopian tube carcinoma represents less than 1% of all gynecologic malignancies and is therefore one of the less common malignancies of the female genital tract. Fallopian tube carcinoma is rarely diagnosed preoperatively and is often mistaken for benign pelvic disease or ovarian cancer. Compared with ovarian carcinoma, fallopian tube cancer more often presents in early stage but seems to have a worse prognosis, stage for stage. Treatment consists of surgical debulking followed by chemotherapy, adjuvant or otherwise. New studies are needed to better delineate the clinical course, prognostic factors, and appropriate chemotherapy recommendations.

Cytologic features of endometrial papillary serous carcinoma.

Endometrial papillary serous carcinoma (EPSC) is an uncommon variant of endometrial carcinoma that histologically resembles ovarian serous carcinoma and has an aggressive clinical course. The cytomorphologic features of 17 patients with histologically confirmed EPSC of the endometrium were reviewed and compared with those of 20 patients with histologically typical endometrial adenocarcinoma (TEC). Preoperative cervicovaginal Papanicolaou smear results were available from 14 of the 17 patients with EPSC; 10 (71%) were positive, 1 (7%) was suspicious and 3 (21%) were negative for malignancy. Initial cervicovaginal smear results were available from all 20 patients with TEC; 7 (35%) were positive, 4 (20%) were atypical or suspicious and 9 (45%) were negative for malignancy. Twelve patients with EPSC had peritoneal washings or fluids examined; seven were positive and five negative. Twelve patients with TEC had peritoneal washings or fluids examined; two (17%) were positive and ten (83%) were negative. The cervicovaginal smears from patients with EPSC revealed numerous large tumor cells (with prominent nucleoli) frequently arranged in papillary clusters with background necrosis and, in two cases, amorphous material suggestive of psammoma bodies. In contrast, the smears of patients with TEC showed small to medium-sized cells with extensive phagocytosis and many background histiocytes. The diagnosis of EPSC should be considered when the cervicovaginal smear contains numerous papillary groups of large tumor cells with macronucleoli but without prominent phagocytosis, especially when structures suggestive of psammoma bodies are present. The peritoneal fluids in these patients are more often positive than in patients with TEC, a finding consistent with the propensity of EPSC to involve peritoneal surfaces.

Postoperative management of patients with stage Ib endometrial carcinoma.

Between 1980 and 1990, 124 patients with Stage Ib endometrioid adenocarcinoma of the endometrium were treated at Massachusetts General Hospital (MGH). Patients were identified from the tumor registry and medical records were retrospectively reviewed. Of the 124 patients, four (3%) developed a recurrence. Eighty-six patients had grade 1 tumors, 32 grade 2 and 6 grade 3. Recurrences developed in two (2%) of the grade 1 tumors, one (3%) of the grade 2, and one (17%) of the grade 3. Of the 86 patients with grade 1 carcinomas, 58 received no adjuvant radiation, 25 received vaginal vault brachytherapy and 3 whole pelvic radiation (WPR). Of the 32 patients with grade 2 tumors, 13 received no adjuvant therapy, 10 vaginal brachytherapy, and 9 WPR. Of the six patients with grade 3 tumors, one received no adjuvant therapy, two vaginal brachytherapy, and three WPR. Of the four women that relapsed, only the patient with grade 3 tumor had been treated with adjuvant radiation (WPR). Three of the four patients recurred at the vaginal vault and all three were salvaged. Stage Ib, grade 1 and 2, endometrioid adenocarcinomas have a good prognosis and adjuvant radiotherapy is not clearly beneficial.

Gray scale ultrasound in adnexal thickening: correlation with laparoscopy.

A retrospective comparison between ultrasound and subsequent laparoscopy was made in 70 female patients to evaluate the sonographic features of minimal pelvic disease (in particular, adnexal thickening). The overall accuracy of sonography as compared with laparoscopy was 75 percent (53 of 70), with a true positive rate of 72 percent (40 of 51) and a true negative rate of 68 percent (13 of 19). In this study the concept of clinical or sonographic adnexal thickening did not correlate with observations at laparoscopy. Of the 7 patients diagnosed by ultrasound as having adnexal thickening, only 1 had pelvic inflammatory disease, whereas the other 6 showed no abnormalities at laparoscopy.

Condyloma acuminatum of the bladder and ureter: case report and review of the literature.

We report on a 56-year-old woman with extensive condyloma acuminatum of the external genitalia and vagina, with spread to and diffuse involvement of the urethra, bladder and distal ureters. A chronic course, failure to respond to conservative measures and evidence of malignant transformation led to radical surgical treatment.

Vaginal adenosis and clear cell carcinoma after 5-fluorouracil treatment for condylomas.

Vaginal adenosis and clear cell adenocarcinoma of the vagina occurred in a 44-year-old woman after treatment for condylomata acuminata. She had no known exposure to diethylstilbestrol (DES) in utero. Biopsy-proven vaginal adenosis appeared 8 months after intravaginal 5-fluorouracil application for recurrent urogenital condylomata acuminata. Forty months later, biopsies showed residual adenosis with foci of clear cell adenocarcinoma. Although clear cell adenocarcinoma is associated with vaginal adenosis and cervical ectropion in DES-exposed women, its occurrence in adenosis after 5-fluorouracil therapy has not been reported to the authors' knowledge. In this report, this rare but serious complication of treatment of condylomata acuminata is highlighted, and the literature regarding the development of non-DES-associated vaginal adenosis is discussed.

Efficacy and hematologic toxicity of salvage chemotherapy following stem cell-supported high-dose chemotherapy in women with recurrent ovarian cancer.

OBJECTIVE: The objective of this study was to determine the efficacy and hematologic toxicity of salvage chemotherapy in patients with recurrent ovarian cancer following high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT). METHODS: A retrospective analysis of 19 Massachusetts General Hospital case records of women with relapsed ovarian cancer following PBSCT was conducted. RESULTS: Between February 1996 and September 1998, 24 women with ovarian cancer were treated with PBSCT. Nine patients were treated with an upfront PBSCT regimen to consolidate first-line chemotherapy and 15 patients were treated with PBSCT after a median of two lines (range: 1-3) of prior chemotherapy. Sixteen patients presented with relapsed disease at a median of 230 days post-PBSCT and 3 patients had persistent disease through high-dose chemotherapy. Each of these 19 patients has been treated with salvage chemotherapy following PBSCT. Patients received one of six different first-line salvage chemotherapy regimens. Sixteen of nineteen patients are alive a median of 383 days (range: 156-868) after relapse following PBSCT. Three patients died of progressive disease at a median of 284 days (range: 224-648) after post-PBSCT relapse. Six patients achieved a complete response, four patients had a partial response, three patients had stable disease, and six patients had progressive disease in response to first-line salvage chemotherapy. Seven patients experienced grade III/IV neutropenia, and three patients experienced grade III/IV thrombocytopenia. CONCLUSIONS: We conclude that in a patient population selected for chemotherapy sensitive and low-volume disease prior to PBSCT, patients with recurrent tumor appear to respond to salvage chemotherapy, and associated hematologic toxicity is acceptable and manageable.

The effect of postsurgical therapy on stage III endometrial carcinoma.

The records of 86 pathologic stage III endometrial carcinoma patients treated at Massachusetts General Hospital between 1974 and 1992 were retrospectively reviewed to identify predictors of poor outcome and to determine the effect of postsurgical therapy on recurrence and survival. Patients underwent TAH/BSO with selective lymphadenectomy and peritoneal washings. Cases prior to 1988 were retrospectively restaged using the FIGO surgical staging criteria. Postoperatively, patients received individualized regimens of EBRT (external beam radiotherapy), brachytherapy, and cytotoxic or hormonal chemotherapy. The 5-year survival and 5-year disease-free survival (DFS) for all patients were 54 and 44%, respectively. Forty-two percent of stage IIIA/B patients recurred in a median time of 14 months. Fifty-four percent of stage IIIC patients recurred in a median time of 16 months. Of patients who recurred, 90% stage IIIA/B and 71% stage IIIC patients recurred at extrapelvic sites. Age greater than 70, high-grade lesions, and fallopian tube metastases were predictive of poor outcome in stage IIIA/B by multivariate analysis. Vascular invasion was the only poor prognostic factor identified by multivariate analysis in stage IIIC disease. No benefit from pelvic EBRT in stage IIIA/B could be identified. Stage IIIC patients had increased DFS and a trend for increased survival with pelvic EBRT. Chemotherapy did not improve survival in either group.

Intraoperative radiation therapy in the treatment of pelvic gynecologic malignancies: a review of fifteen cases.

OBJECTIVE: The aim of this study was to review the experience with intraoperative radiation therapy (IORT) in the treatment of gynecologic pelvic malignancies at the Massachusetts General Hospital. METHODS: From July 3, 1996, through July 28, 1999, 15 patients were treated with IORT for gynecologic malignancies in a dedicated IORT operating room suite at the Massachusetts General Hospital. Hospital medical records, radiation oncology records, and office charts were reviewed on all patients treated with IORT. IORT was given in the presence of positive surgical margins and where the doses needed for adjuvant postoperative external beam radiotherapy (EBRT) would exceed those tolerated by normal structures. One patient presented with primary disease and 14 with local or regional recurrence. Follow-up time ranged from 3 to 36 months. RESULTS: Treatment in conjunction with IORT included surgery only (7 patients); preoperative EBRT, preoperative brachytherapy, and surgery (1 patient); preoperative chemotherapy and surgery (2 patients); and surgery and postoperative chemotherapy (5 patients). IORT doses ranged from 10 to 22.5 Gy. At the completion of this review, 4 patients (26.6%) have died, 6 (40%) are alive and free of disease, and 5 (33%) are alive with disease persistence or relapse. Of the 10 patients with gross total resection, 5 are alive and free of disease. Of the 5 women with gross residual disease at the time of IORT, only 1 is alive and free of disease. CONCLUSIONS: The volume of residual disease prior to IORT may be an important prognostic indicator for disease relapse. Both local recurrence and distant metastasis were more common among patients with gross residual disease at the time of IORT. Our institutional experience with IORT further supports the importance of optimal surgical resection.

Surgical stage IV endometrial carcinoma: a study of 47 cases.

Between 1976 and 1991, 47 patients with surgical Stage IV endometrial carcinoma were treated. Patients were identified from the tumor registry and charts were retrospectively reviewed. Surgical curves using the Kaplan-Meier product-limit method and Cox regression analysis were used to identify independent prognostic factors. Overall, median survival was only 12 months. Using univariate analysis there was no statistically significant difference in survival between age (P = 0.41), histology (P = 0.54), grade (P = 0.91), disease site (P = 0.32), or clinical stage (P = 0.87). In patients whose disease was surgically cytoreduced, the median survival was 18 months compared to 8 months in those who did not undergo surgery (P = 0.0001). Evaluation of other treatment modalities by univariate analysis revealed improved survival in those patients who received cyclophosphamide, doxorubicin, and cisplatin (P = 0.0007), decreased survival in those who received radiation therapy compared to surgery (P = 0.023), and no statistically significant difference in survival with progestins. By multivariate analysis successful cytoreduction was the only statistically significant prognostic variable (P = 0.04). This 15-year retrospective review confirms that prognosis for women with Stage IV endometrial cancer is extremely poor. However, if hysterectomy with cytoreduction is feasible, surgery should be performed because survival may be improved.

Stage IB and IIA cervical cancer with negative lymph nodes: the role of adjuvant radiotherapy after radical hysterectomy.

The records of 171 patients with lymph node-negative stage IB and IIA cervical cancer primarily treated with radical hysterectomy and pelvic lymphadenectomy from 1974 to 1992 were retrospectively reviewed to identify poor prognostic factors and evaluate the role of adjuvant pelvic radiotherapy. One hundred sixteen patients (68%) were treated with radical hysterectomy alone (RH) and 55 patients (32%) received adjuvant radiotherapy (RH + RT). Factors predictive of recurrence for the entire group of patients included lymph-vascular space invasion (LVSI) (P = 0.003) and grade 3 histology (P = 0.04). Patients receiving RH + RT were older and more likely to have outer third cervical wall invasion, LVSI, positive margins, > or =2 cm pathologic tumor size, and >4 cm clinical tumor size (all P < 0.05). Overall, 28 patients (16%) developed recurrent disease with no difference between RH and RH + RT groups. After controlling for confounding variables, patients with LVSI who received RH + RT were less likely to develop disease recurrence than patients receiving RH alone (P = 0.04). LVSI is an important prognostic variable in lymph node-negative stage IB and IIA cervical cancer. Although adjuvant pelvic radiotherapy may decrease the risk of recurrence in patients with LVSI, the majority of patients with negative lymph nodes may be treated with radical surgery alone.

Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity.

Human ovarian carcinomas express the CA-125, HER2/neu, and MUC1 tumor-associated Ags as potential targets for the induction of active specific immunotherapy. In the present studies, human ovarian cancer cells were fused to human dendritic cells (DC) as an alternative strategy to induce immunity against known and unidentified tumor Ags. Fusions of ovarian cancer cells to autologous DC resulted in the formation of heterokaryons that express the CA-125 Ag and DC-derived costimulatory and adhesion molecules. Similar findings were obtained with ovarian cancer cells fused to allogeneic DC. The fusion cells were functional in stimulating the proliferation of autologous T cells. The results also demonstrate that fusions of ovarian cancer cells to autologous or allogeneic DC induce cytolytic T cell activity and lysis of autologous tumor cells by a MHC class I-restricted mechanism. These findings demonstrate that fusions of ovarian carcinoma cells and DC activate T cell responses against autologous tumor and that the fusions are functional when generated with either autologous or allogeneic DC.

Epithelial ovarian tumors of borderline malignancy: long-term follow-up.

Thirty-nine patients underwent primary surgery for epithelial ovarian tumors of low malignant potential at the Massachusetts General Hospital between 1970 and 1980. Eighty-five percent of patients were found to have Stage I disease and 15% were found to have Stage III disease. Fifty-four percent of patients had a tumor with serous histology, 39% had a tumor with mucinous histology, and the remainder of patients had tumors with an endometrioid or mixed-cell type. Second malignancies and benign ovarian tumors were frequently found concomitantly with the borderline tumors or in follow-up. Gastrointestinal and endometrial adenocarcinomas were the most common second malignancies and were frequently found associated with a borderline tumor of serous histology. Follow-up was available in all 39 patients (100%). Mean time of follow-up was 11.8 years. Sixty-nine percent of patients are clinically without evidence of disease with a mean follow-up of 14.7 years, 23% died of other causes, 5% died of disease, and 3% died with disease and sepsis. All patients dying with disease did so within 7.3 years of their primary surgery. Seven patients underwent conservative surgery, defined as preservation of some ovarian tissue. Six of 7 patients are clinically free of disease with a mean follow-up of 14.6 years; 1 patient died of other causes. No patients treated conservatively had a recurrence of their disease.

Combination chemotherapy in advanced adenocarcinoma of the fallopian tube.

Advanced adenocarcinoma of the fallopian tube has a poor prognosis, with 5-year survival rates commonly less than 20%. Since 1980, we have managed 12 patients with disseminated tumor with combination chemotherapy following surgical cytoreduction. Analogous to the International Federation of Gynecology and Obstetrics staging of ovarian carcinoma, 3 patients were classified in Stage II, 8 in Stage III, and 1 in Stage IV. Ten patients received cisplatin-containing regimens. The 3 Stage II patients, without measurable disease after primary surgery, had an indeterminate response to chemotherapy. In Stages III-IV there were 4 complete responses (3 confirmed by second-look laparotomy) and 2 partial responses, for an overall response rate of 67%. Disease progressed in 2 patients and was stable in 1 patient. After median follow-up of 3.5 years, 4 of the Stage III-IV patients have no evidence of disease, 1 is alive with disease, and 4 are dead.